Project Summary/Abstract Sudden cardiac death (SCD) due to ventricular tachyarrhythmias (VT) is the leading cause of death in the United States. Dysregulation of the autonomic nervous system, specifically sympathoexcitation, plays a major role in the pathophysiology of cardiac arrhythmias secondary to ischemic heart disease. The spinal cord serves as a major nexus point for control of sympathetic reflexes to the heart. However, there are major gaps in the understanding of regulation of cardiac excitability at the level of the spinal cord. Spinal neuromodulation therapies- spinal cord stimulation (SCS) and dorsal root ganglion (DRG) stimulation, show promise towards reducing VTs, but the mechanisms underlying the therapeutic benefits of these innovative approaches remain largely unknown. The goal of this proposal is to determine how the spinal cord processes cardiac afferent impulses during myocardial ischemia and to explain how neuromodulation therapies reduce ventricular arrhythmias, leading to their more effective and expansive use. In this proposal, it is hypothesized that unique cardiospinal neural networks integrate the cardiac afferent signals during myocardial ischemia (MI) and control sympathoexcitation, thereby modulating arrhythmogenesis. Further, MI triggers pathologic remodeling of cardiospinal neural circuits, which increase myocardial sympathoexcitation. SCS and DRG stimulation, reduce sympathetic output through induction of GABA signaling pathways in the spinal cord, reducing ventricular excitability and arrhythmias after chronic MI. Importantly, preliminary functional data shows anti-arrhythmic effects of SCS during acute I/R were abolished in the presence of GABA receptor antagonists, supporting the hypothesis. Real Time PCR also shows expression of GABAA and GABAB receptors is increased by SCS therapy in spinal cord during MI. Thus, modulation of cardiac afferent neural inputs to the spinal cord presents a novel target for suppression of excessive sympathetic reflex activation and cardiac arrhythmias. To mechanistically understand the therapeutic potential of such approaches, proposed experiments will evaluate the effects of neuromodulation on cardiospinal neural network and ventricular excitability. The proposed studies will evaluate novel mechanisms of regulation of cardiac excitability at the spinal level. Specific aims 1 is designed to provide a mechanistic understanding of the role of spinal cord processing of afferent cardiac neural inputs. Electrophysiological and neurochemical alterations in cardiospinal neural network in chronic MI will be compared with healthy hearts when subjected to additional cardiac stress (acute ischemia/reperfusion). Molecular mechanisms through which chronic MI induces pathologic remodeling of the cardiospinal neural network will be characterized. In specific aim 2 and 3, mechanisms by which SCS and DRG stimulation reduce cardiospinal neural network remodeling and decrease myocardial sympathoexcitation in chronic MI will be identified. The proposed studies will provide the framework to maximize the therapeutic potential of neuromodulation in mitigation of cardiac and neural remodeling in chronic MI.